Experiments performed in animal models have established that administration of angiogenic growth factors as recombinant proteins or by gene transfer promotes neovascularization of ischemic tissues. Preliminary investigations in patients with critical limb ischemia suggest that this strategy, termed therapeutic angiogenesis, may yield potential clinical benefit, including relief of rest pain and restoration of tissue integrity. Follow-up studies of these patients and preliminary animal studies suggest that therapeutic angiogenesis may also lead to recovery of nerve function in patients and animals with ischemic peripheral neuropathy. Accordingly, this Proposal has been designed to systematically investigate the impact of therapeutic angiogenesis on ischemic peripheral neuropathy. The proposed experiments have been designed to test specific hypotheses, organized according to three Specific Aims. Specific Aim 1 will determine the impact of therapeutic angiogenesis on ischemic peripheral neuropathy, using a rabbit model of hindlimb ischemia. These experiments will evaluate what has been considered to be a relatively endothelial cell (EC)-specific cytokine, vascular endothelial growth factor (VEGF), as well as more pleiotropic angiogenic growth factors. The impact of angiogenesis inhibitors on endogenous recovery of nerves injured due to ischemia will be investigated as well. Specific Aim 2 will employ animal models with experimentally induced diabetes to determine the impact of angiogenic growth factors on peripheral neuropathy, with and without macrovascular insufficiency. The response of ischemic neuropathy to neurotrophins will also be investigated in these animal models. The third Specific Aim is to investigate the cellular basis for modulation of ischemic peripheral neuropathy by therapeutic angiogenesis. These experiments will determine whether the impact of VEGF on ischemic neuropathy is limited to indirect effects achieved by enhanced neovascularization, or whether VEGF may directly modulate non-vascular neural elements. The extent to which angiogenic growth factors and ischemia modulate expression of endogenous neurotrophins will be investigated as well. Finally, mechanisms responsible for peripheral nerve recovery in response to angiogenic cytokines will be studied for contribution of bone-marrow derived endothelial precursors to putative neovascularization of the vasa nervorum. The experiments outlined in this Proposal are anticipated to provide new insights into the fundamental relationship between vascular and peripheral nerve integrity, and suggest novel therapeutic strategies to address a clinical disorder that accounts for considerable morbidity.